When Kraepelin first identified the disorder that he called "dementia praecox," he was referring to a syndrome similar to the dementias of later life but beginning at a relatively early age. Since that time, several changes have occurred in the concept of schizophrenia. In stressing the importance of "fundamental symptoms" and minimizing the importance of a deteriorating course, Bleuler broadened the concept of schizophrenia to include milder cases. Some investigators have added a requirement of "clear consciousness," usually defined as intact orientation and memory. A distinction between organic and functional psychoses has been embedded in our nomenclature during recent decades, also serving to preclude conceptualizing schizophrenia as organic in origin (see the Diagnostic and Statistical Manual of Mental Disorders, 3rd edition). Finally, during recent years investigators have emphasized the importance of "positive" symptoms, such as delusions and hallucinations, in the definition of schizophrenia, primarily because they are easy to identify and define reliably. The increased interest in positive symptoms has led to a deemphasis of the importance of more "negative" symptoms, such as affective flattening or impoverished thinking, which are similar to those occurring in typical dementias. Andreasen, et al. Am. J. Psychiatry 139:3 March 1982, 297-301. Diagnostic criteria for distinguishing positive schizophrenia and negative schizophrenia is disclosed by Andreasen and Olsen, Arch Gen Psychiatry Vol. 39, p. 789-794 July 1982.
The use of adinazolam, 8-chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzo diazepine, in the treatment of schizophrenia, primarily for the negative symptoms of schizophrenia is the prior invention of another. The use of adinazolam and some other 1-(nitrogen-containing group) triazolobenzodiazepines and their pharmacologically acceptable salts for treating psychosis and schizophrenia is disclosed in U.S. Pat. No. 4,472,397.
O. Lingjaerde concludes in "Effect of the Benzodiazepine Derivative Estazolam in patients with Auditory Hallucinations. A Multicentre Double-Blind, Cross-Over Study", Acta Psychiat. Scand. 65:339-354 (1982) that estazolam (as an addition to neuroleptics) had a significantly better effect than placebo on the global clinical state, on the frequency of, and attitude towards the hallucinations, and also on the single symptoms "compulsive thoughts" and "visual hallucinations" (items in the Comprehensive Psychopathological Rating Scale). Professor Lingjaerde also reported at p. 353:
"In a recent survey of the literature (Lingjaerde (1982) it is concluded that a therapeutic effect in schizophrenia has been demonstrated in controlled trials for at least four benzodiazepines: chlorodiazepoxide, diazepam, alprazolam, and estazolam, but most other benzodiazepines have not been given adequate trial." PA1 "To date, double-blind studies, with one exception, have not shown benzodiazepines to be effective in schizophrenia. The exception is the study of Kellner and associates. Using a model of intensive design, they studied three patients who were repeatedly switched from chlorodiazepoxide to placebo, while an antipsychotic drug was continued . . . ".
However, according to Lingjaerde the reference to alprazolam is an error and should have been lorazepam. In fact, Professor Lingjaerde stated in a letter in August of 1984 that he had never seen any paper on the possible effect of alprazolam in schizophrenia--such a study would seem well worth performing, considering the similarity between alprazolam and estazolam.
The citation "Lingjaerde (1982): `Benzodiazepines in the Treatment of Schizophrenia` (in press)" in Acta Psychiat. Scand. 65:339-354 (1982) was published as an article in the book The Benzodiazepines: From Molecular Biology to Clinical Practice, edited by E. Costa, Raven Press, New York, pp. 369-381 (LC Number QV 77.9 34792 1981) and contains the same error at p. 377 regarding alprazolam instead of lorazepam.
In a review article entitled "Drug Treatment of Acute Schizophrenia", pp. 237-280 in Schizophrenia and Affective Disorders, edited by A. Rifkin, John Wright.PSG, Inc. (1983), Siris S. G. et al reported:
The compounds of Formula I have been variously indicated for the management of anxiety disorders, sedative, tranquilizer, muscle relaxant and anti-depressant activity.